Pyrimidine analogs are known to be effective chemotherapeutic agents. Gemcitabine, an analog of cytidine with a modified sugar, a 2′,2′-difluorodeoxyribose, is a chemotherapeutic drug currently approved as single therapy for the treatment of pancreatic cancer, and as part of combination chemotherapy regimens for the treatment of non-small cell lung cancer, breast cancer and ovarian cancer (Gemzar (gemcitabine HCl) for injection. 2007. Eli Lilly and Company.) The following properties make gemcitabine an effective anticancer agent: (1) it is an inhibitor of ribonucleoside diphosphate reductase (RR), the enzyme that catalyses the conversion of diphosphorylated ribonucleosides to diphosphorylated deoxyribonucleosides; (2) it acts as a DNA chain terminator; and (3) it is not a substrate for pyrimidine nucleoside phosphorylase, hence precluding the breakdown of a nucleoside into a separate base and a sugar moiety (Plunkett, W., et al., “Gemcitabine: Metabolism, Mechanism of Action and Self-Potentiation,” Semin. Oncol. 22(4; Suppl 11):3-10, 1995; Mini, E., et al., “Cellular Pharmacology of Gemcitabine,” Ann. Oncol. 17 (Suppl 5) v7-v12. 2006).
Two other cytidine analogs, 5-azacytidine and 5-azadeoxycytidine, are approved for the treatment of hematologic tumors, and act by inhibiting DNA methyl transferase (DNMT), the enzyme required for DNA methylation. The 5-azacytidine analogs are known to be unstable in water and cleaved at the 6-position of the base (Christman, J. K., “5-azacytidine and 5-aza-2′-deoxycytidine as Inhibitors of DNA Methylation: Mechanistic Studies and Their Implications for Cancer Therapy, Oncogene 21:5483-5495, 2002.)
Trifluridine, 5-trifluorothymidine, has also demonstrated antineoplastic activity and is thought to act by inhibiting thymidilate synthase. However, its development as an antineoplastic agent has been hampered by its short half-life (12 minutes). Co-administration of trifluridine with a thymidine phosphorylase inhibitor has resulted in more acceptable pharmacokinetics with mean half-lives between 1.37 and 1.57 hours (Hong D S, Abbruzzese J L, Bogaard K et al. Phase I study to determine the safety and pharmacokinetics of oral administration of TAS-102 in patients with solid tumors. Cancer. 2006; 15(107):1383-1390.)
One approach that has been proposed to prolong the circulatory half-life of pyrimidine analogs is to generate a prodrug that would result in a more hydrophobic molecule that could be formulated in a lipid based nanoformulation and rapidly release the active drug upon exposure to an aqueous environment at the tumor site. Conjugating a drug that has a short half-life with a lipophilic moiety such as, for example, trimethylsilyl (TMS) or other silyl moieties, and formulating the lipophilic prodrug in a hydrophobic milieu may result in a prolonged circulating half-life.
There continues to exist a need for novel cancer therapeutics with improved efficacy, safety, and/or pharmacokinetic profiles. The invention provides novel silylated-pyrimidine prodrugs and compositions for the treatment of cancer.